Pyrazolopyridylpyridazinone derivatives and process for the preparation thereof

ABSTRACT

Novel pyrazolopyridylpyridazinone derivatives characterized by being represented by general formula (1) and pharnacologically acceptable salts thereof, which exhibit a phosphodiesterase inhibiting activity and have a selective potent bronchodilating effect on the respiratory tract; a process for the preparation of them; and bronchodilators containing the same as the active ingredient; wherein R 1  is C 1 -C 4  lower alkyl or C 3 -C 6  cycloalkyl; and R 2 , R 3 , R 4  and R 5  are each independently hydrogen, C 1 -C 4  lower alkyl or phenyl, or alternatively R 3  and R 5  may be united to form a double bond.

TECHNICAL FIELD

The present invention relates to novel pyrazolopyridinepyridazinonederivatives with phosphodiesterase-inhibiting activity and withselective-to-respiratory tract and potent bronchodilating effect andprocess for preparing the same.

BACKGROUND TECHNOLOGIES

Compounds with dihydropyridazinone and pyridazinone groups substitutedat 3-position of pyrazolopyridine ring have been disclosed in JapaneseUnexamined Patent publication Nos. Hei 2-243689 and Hei 4-253978.However, with the compounds claimed in these unexamined patentpublications, substituents at 2-position of pyrazolopyridine ring arelimited to aryl groups such as benzene derivatives, including noinventive compounds wherein they are alkyl groups. Also,pyrazolopyridine derivatives with bronchodilating effect are disclosedin Japanese Unexamined Patent Publication No. Hei 8-12673, but compoundsdisclosed therein have quite different structure from that of theinventive compounds.

Since it was discovered that the bronchodilating effect is causedthrough enhanced cyclic AMP and GMP in cells, enzymes that decomposecyclic AMP and GMP and inhibiting drugs of phosphodiesterase areattracting an attention as bronchodilator. While theophylline ismentioned for a common drug as an inhibiting drug of phosphodiesterase,theophylline has low selectivity to target organ. For this reason, whenusing theophylline to asthmatic patients for the purpose ofbronchodilating effect, undesirable effects such as increased heartrate, vomition and central action occur very frequently as well.Developing a drug that acts selectively to respiratory tract being atarget organ and expresses the bronchodilating effect via potentphosphodiesterase-inhibiting activity is being desired strongly as anideal drug with low side effect.

As a result of diligent studies an a compound withphosphodiesterase-inhibiting activity and with selective-to-respiratorytract and potent bronchodilating effect, the inventors have found thatnovel pyrazolopyridinepyridazinone derivatives with different structurefrom that of bronchodilators known so far have high safety, too, andhave selective-to-respiratory tract and potent bronchodilating effect,leading to the completion of the invention.

Namely, the invention provides pyrazolopyridinepyridazinone derivativescharacterized by being represented by a general formula (1)

[wherein R¹ denotes a lower alkyl group with carbon atoms of 1 to 4 orcycloalkyl group with carbon atoms of 3 to 6, and R², R³, R⁴ and R⁵denote identically or differently hydrogen atoms, lower alkyl groupswith carbon atoms of 1 to 4 or phenyl groups, or R³ and R⁵ may combineto form a double bond], pharmacologically acceptable salts, andbronchodilator having at least one or more kinds of them as effectiveingredients.

For the pharmacologically acceptable salts of the compounds representedby the general formula (1) in the invention, acid adducts likehydrochloride, hydrobromide, citrate, methanesulfonate and tartrate arementioned.

Moreover, in the general formula (1) of the invention, “lower alkylgroup” indicates straight chain or branched hydrocarbons with carbonatoms of 1 to 4 such as methyl, ethyl and propyl and, for “cycloalkylgroup”, cyclic hydrocarbons with carbon atoms of 3 to 6 are mentioned.Moreover, for “halogen atom”, chlorine, bromine and iodine atoms arementioned.

According to the invention, compounds with R³ and R⁵ not forming adouble bond among compounds represented by the general formula (1)aforementioned, i.e. compounds represented by a general formula (1a)

[wherein R¹ is as described above, and R², R⁴, R⁶ and R⁸ denoteidentically or differently hydrogen atoms, lower alkyl groups withcarbon atoms of 1 to 4 or phenyl groups], can be prepared by reactingcompounds represented by a following general formula (6) with hydrazine.

[wherein R¹, R², R⁴, R⁶ and R⁸ are as described above].

The reaction can be conducted at room temperature to solvent-refluxingtemperature as a reaction temperature in an organic solvent, forexample, benzene, toluene, acetic acid, ethanol or the like. At thistime, ethanol is preferable as a reaction solvent and the reactiontemperature is preferable to be refluxing temperature under heat.

Moreover, compounds with R³ and R⁵ combined to form a double bond in thegeneral formula (1), i.e. compounds represented by a general formula(1c)

[wherein R¹, R² and R⁴ are as described above], can be prepared byoxidizing compounds represented by a general formula (1b)

[wherein R¹, R² and R⁴ are as described above].

It is preferable to conduct the reaction by reacting with bromine in asolvent of acetic acid, and the reaction temperature is preferable to be50 to 60° C.

The compounds represented by the general formula (6) aforementioned canbe prepared through following three routes.

In the synthetic route 1, compounds represented by a general formula (5)

[wherein R¹, R², R⁴, R⁶ and R⁸ are as described above, and R⁷ denotes alower alkyl group with carbon atoms of 1 to 3], can be prepared byreacting compounds represented by a general formula (2) with compoundsrepresented by a general formula (4)

[wherein R¹, R² and R⁶ are as described above].

[wherein X denotes a halogen atom, and R⁴, R⁷ and R⁸ are as describeabove].

It is preferable to conduct the reaction at 0° C. to solvent-refluxingtemperature, though the reaction temperature is not restrictedparticularly, in the presence of inorganic base such as potassiumt-butoxide or potassium hydride, preferably sodium hydride, usingtetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane, preferablydimethylformamide.

In the synthetic route 1, the compounds of general formula (6)

[wherein R¹, R², R⁴, R⁶ and R⁸ are as described above], can be preparedby hydrolyzing the compounds represented by the general formula (5)aforementioned.

In the case of acid catalyst, it is preferable to conduct the hydrolysisby heating to 80 to 120° C., using hydrochloric acid or hydrobromicacid. Moreover, in the case of alkali catalyst, it is preferable toconduct at room temperature in an alcoholic solvent such as methanol orethanol or in a solvent such as tetrahydrofuran or dimethylformamide,using aqueous solution of sodium hydroxide or aqueous solution ofpotassium hydroxide.

In the synthetic route 2, compounds represented by a general formula(16)

[wherein R¹ and R² are as described above, and R denotes a lower alkylgroup with carbon atoms of 1 to 3], can be prepared by reactingcompounds represented by a following general formula (2a) with compoundsrepresented by a general formula (3)

[wherein R¹ and R² are as described above].

CO(OR)₂   (3)

[wherein R is as described above].

It is preferable to conduct the reaction by refluxing under heat as areaction temperature in the presence of inorganic base such as potassiumt-butoxide or potassium hydride, preferably sodium hydride, usingsolvent amount of the compounds of general formula (3).

In the synthetic route 2, compounds represented by a general formula(17)

[wherein R, R¹, R², R⁴, R⁷ and R⁸ are as described above], can beprepared by reacting compounds represented by the general formula (16)with compounds represented by the general formula (4)

[wherein R, R¹ and R² are as described above].

[wherein X, R⁴, R⁷ and R⁸ are as described above].

It is preferable to conduct the reaction at 0° C. to solvent-refluxingtemperature, though the reaction temperature is not restrictedparticularly, in the presence of inorganic base such as potassiumcarbonate, potassium t-butoxide or potassium hydride, preferably sodiumhydride, using tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane,preferably dimethylformamide as a reaction solvent.

In the synthetic route 2, compounds represented by a general formula(6a)

[wherein R¹, R², R⁴ and R⁸ are as described above], can be prepared byhydrolyzing and decarboxylating the compounds represented by the generalformula (17) aforementioned.

In the case of acid catalyst, it is preferable to conduct the hydrolysisand decarboxylation by heating to 80 to 120° C., using hydrochloric acidor hydrobromic acid. Moreover, in the case of alkali catalyst, it ispreferable to conduct at room temperature in an alcoholic solvent suchas methanol or ethanol or in a solvent such as tetrahydrofuran ordimethylformamide, using aqueous solution of sodium hydroxide or aqueoussolution of potassium hydroxide.

In the synthetic route 3, compounds represented by a general formula (9)

[wherein R¹, R² and R⁶ are as described above, R¹¹ denotes a lower alkylgroup with carbon atoms of 1 to 3, and (n, m) denotes a combination ofintegers of (1, 3) or (2, 2)], can be prepared by reacting compoundsrepresented by a general formula (7) with compounds represented by ageneral formula (8).

[wherein X, R¹, R² and r⁶ are as described above].

CH_(n)(CO₂R¹¹)_(m)   (8)

[wherein combination of (n, m) and R¹¹ are as described above].

It is preferable to conduct the reaction at 0° C. to solvent-refluxingtemperature, though the reaction temperature is not restrictedparticularly, in the presence of inorganic base such as potassiumcarbonate, potassium t-butoxide or potassium hydride, preferably sodiumhydride, using tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane,preferably dimethylformamide as a reaction solvent.

In the synthetic route 3, compounds represented by a general formula(6b)

[wherein R¹, R² and R⁶ are as described above], can be prepared byhydrolyzing and decarboxylating the compounds represented by the generalformula (9) aforementioned.

In the case of acid catalyst, it is preferable to conduct the hydrolysisand decarboxylation by heating to 80to 120° C., using hydrochloric acidor hydrobromic acid. Moreover, in the case of alkali catalyst, it ispreferable to conduct at room temperature in an alcoholic solvent suchas methanol or ethanol or in a solvent such as tetrahydrofuran ordimethylformamide, using aqueous solution of sodium hydroxide or aqueoussolution of potassium hydroxide.

Best embodiment to put the invention into practice

In following, the invention will be illustrated based on concreteexamples, but the invention is not confined to these examples. Moreover,when the compounds of the invention have asymmetric carbons at4-position and 5-position of dihydropyridazinone ring, there existoptical isomers, which are all included in the invention.

EXAMPLE 1 Methyl2-methyl-3-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3-oxopropionate

2-Methyl-3-propionylpyrazolo[1,5-a]pyridine (5.28 g) was dissolved intodimethyl carbonate (100 ml), and, after adding sodium hydride (3.37 g),the mixture was refluxed for 8 hours under heat. Under cooling in waterbath, acetic acid was added, then, following dilution with water, themixture was extracted with methylene chloride. After the organic layerwas dried over anhydrous sodium sulfate, solvent was distilled off underreduced pressure and the residue was purified by means of silica gelcolumn chromatography (developing solvent, ethylacetate:n-hexane=1:3˜1:1) to obtain aimed product (5.13 g) as a yellowoily product.

EXAMPLES 2 THROUGH 9

Similarly to Example 1, following compounds were obtained (Table 1).

TABLE 1

Example R¹ R² R Yield (%) Property 2 Me Et Me 91 Pale yellow oilyproduct 3 Et Me Me 93 Pale yellow oily product 4 Pr Me Me 54 Yellow oilyproduct 5 i-Pr H Me 94 Pale yellow oily product 6 i-Pr Me Me 91 Brownoily product 7 i-Pr Et Me 87 Yellow oily product 8 cyclo-Pr Me Me 46Brown oily product

EXAMPLE 9 Ethyl4-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-3-methoxycarbonyl-3-methyl-4-oxobutyrate

The compound (5.13 g) of Example 1 was dissolved into DMF (70 ml) and,after adding sodium hydride (1.00 g), the mixture was stirred for 1 hourat room temperature. This was cooled in ice bath and ethyl2-bromoacetate (2.77 ml) was added. After stirring for 18 hours untilthe temperature rose to room temperature, saturated aqueous solution ofammonium chloride was added and diluted with water, which was extractedwith ether. After the organic layer was washed with water and withsaturated brine and dried over anhydrous sodium sulfate, solvent wasdistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (developing solvent, ethylacetate:n-hexane=1:2) to obtain aimed product (4.63 g) as a yellow oilyproduct.

EXAMPLES 10 THROUGH 16

By conducting similarly to Example 9 using the compounds of Examples 2through 8 as raw materials and using ethyl 2-bromoacetate, methyl2-bromoacetate or methyl 2-bromopropionate, following compounds whereobtained (Table 2).

TABLE 2

Example R¹ R² R⁴ R⁷ R⁸ R Yield (%) Property 10 Me Et H Me H Me 78 Yellowoily product 11 Et Me H Et H Me 70 Pale yellow oily product 12 Pr Me HEt H Me 85 Yellow oily product 13 i-Pr H Me Me H Me 77 Pale yellow oilyproduct 14 i-Pr Me H Et H Me 69 Pale yellow oily product 15 i-Pr Et H EtH Me 69 Yellow oily product 16 cyclo-Pr Me H Et H Me 37 Yellow oilyproduct

EXAMPLE 174-(2-Methylpyrazolo[1,5-a]pyridine-3-yl)-3-methyl-4-oxobutyric acid

The compound (4.63 g) of Example 9 was dissolved into 47% hydrobromicacid (50 ml) and the solution was refluxed for 1 hour under heat. Thiswas poured into ice water and extracted with methylene chloride. Afterthe organic layer was dried over anhydrous sodium sulfate, solvent wasdistilled off under reduced pressure. The residue was purified by meansof silica gel column chromatography (developing solvent, methylenechloride:ethanol=10:1) to obtain aimed product (2.76 g) as purplepowder.

EXAMPLES 18 THROUGH 24

By conducting similarly to Example 17, following compounds were obtained(Table 3).

TABLE 3

Ex- Yield ample R¹ R² R⁴ R⁸ (%) Property 18 Me Et H H 80 Brown amorphousmaterial 19 Et Me H H 90 Brown amorphous material 20 Pr Me H H 58 Paleyellow amorphous material 21 i-Pr H Me H 99 Pale pink powder 22 i-Pr MeH H 53 Colorless powder 23 i-Pr Et H H 65 Pale yellow amorphous material24 cyclo-Pr Me H H 60 Brown amorphous material

EXAMPLE 25 Methyl4-(2-isopropylpyrazolo[1,5-a]pyridine-3-yl)-3-phenyl-4-oxobutyrate

2-Isopropyl-3-phenacylpyrazolo[1,5-a]pyridine (1.90 g) was dissolvedinto DMF (30 ml), and, after adding sodium hydride (0.35 g), the mixturewas stirred for 0.5 hours at room temperature. Methyl 2-bromoacetate(1.36 g) was added, and, after stirring the mixture for 3 hours at roomtemperature, saturated aqueous solution of ammonium chloride was addedand diluted with water, which was extracted with ether. After theorganic layer was washed with water and with saturated brine and driedover anhydrous sodium sulfate, solvent was distilled off under reducedpressure. The residue was purified by means of silica gel columnchromatography (developing solvent, ethyl acetate:n-hexane=1:3) toobtain aimed product (1.58 g) as a yellow oily product.

EXAMPLE 264-(2-Isopropylpyrazolo[1,5-a]pyridine-3-yl)-3-phenyl-4-oxobutyric acid

The compound (1.58 g) of Example 25 was dissolved into ethanol (15 ml),and, after adding IN aqueous solution of sodium hydroxide (5 ml), themixture was stirred for 1 hour at room temperature. water was added tothe reaction liquor, then 10% hydrochloric acid was added to make pH 3,which was extracted with methylene chloride. After the organic layer wasdried over anhydrous sodium sulfate, solvent was distilled off underreduced pressure to obtain aimed product (1.50 g) as colorless powder.

EXAMPLE 27 Ethyl2,2-diethoxycarbonyl-4-(2-isopropylpyrazolo-[1,5-a]pyridine-3-yl)-3-methyl-4-oxobutyrate

Triethoxycarbonylmethane (1.53 g) was dissolved into DMF (20 ml), and,after adding sodium hydride (0.28 g), the mixture was stirred for 0.5hours at room temperature.3-(2-Bromo-propionyl)-2-isopropylpyrazolo[1,5-a]pyridine (1.77 g) wasadded and the mixture was stirred for 1 hour at room temperature, andthen further stirred for 7 hours by heating to 80 to 100° C. Saturatedaqueous solution of ammonium chloride was added to the reaction liquor,which was diluted with water, then extracted with ether. After theorganic layer was washed with water and with saturated brine and driedover anhydrous sodium sulfate, solvent was distilled off under reducedpressure and the residue was purified by means of silica gel columnchromatography (developing solvent, ethyl acetate:n-hexane=1:2) toobtain aimed product (0.67 g) as a yellow oily product.

EXAMPLE 28 Ethyl2-ethoxycarbonyl-4-(2-isopropylpyrazolo[1,5-a]-pyridine-3-yl)-4-oxobutyrate

Sodium (0.10 g) was dissolved into ethanol (4 ml) and diethyl malonate(0.71 g) was added at room temperature. After stirring for 20 minutes at50° C., a solution of3-(2-bromoacetyl)-2-isopropylpyrazolo[1,5-a]pyridine (1.06 g) in ethanol(6 ml) was added and the mixture was stirred for 75 minutes at 80° C.The reaction liquor was concentrated, and, water and ethyl acetate wereadded to the residue to separate the organic layer. After the organiclayer was washed with water and with saturated brine and dried overanhydrous sodium sulfate, solvent was distilled off and the residue waspurified by means of silica gel column chromatography (developingsolvent, ethyl acetate, n-hexane=1:3) to obtain aimed product (0.44 g)as pale yellow powder.

EXAMPLE 294-(2-Isopropylpyrazolo[1,5-a]pyridine-3-yl)-3-methyl-4-oxobutyric acid

By conducting similarly to Example 17, using the compound (0.67 g) ofExample 27, same compound (0.31 g) as that of Example 21 was obtained aspale yellow amorphous material.

EXAMPLE 30 4-(2-Isopropylpyrazolo[1,5-a]pyridine-3-yl)-4-oxobutyric acid

By conducting similarly to Example 17, using the compound (0.72 g) ofExample 28, aimed compound (0.52 g) was obtained as colorless powder.

EXAMPLE 316-(2-methylpyrazolo[1,5-a]pyridine-3-yl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone

The compound (2.76 g) of Example 17 and hydrazine monohydrate (0.90 g)were dissolved into ethanol (30 ml), and the solution was refluxed for 3hours under heat. The reaction liquor was submitted to distillationunder reduced pressure, and the residue was purified by means of silicagel column chromatography (developing solvent, methylenechloride:ethanol=10:1) to obtain aimed product (2.04 g) as colorlesspowder. When recrystallizing from isopropyl ether, this gave colorlessprismatic crystals.

Melting point:146˜147° C.

Elemental analysis (%): As C₁₃H₁₄N₄O

C H N Calcd.: 64.45 5.82 23.12 Found: 64.28 5.87 22.84

EXAMPLES 32 THROUGH 40

By conducting similarly to Example 31, following compounds were obtained(Table 4).

TABLE 4

Elemental analysis Ex- M.P. (° C.) calcd./found ample R¹ R² R⁴ R⁶ R⁸Yield (%) (Recryst. solvent) C, H, N 32 Me Et H H H 80 138˜140 C₁₄H₁₆N₄Oi-Pr₂O 65.61 6.29 21.86 65.70 6.31 21.72 33 Et Me H H H 79 131˜132C₁₄H₁₆N₄O i-Pr₂O 65.61 6.29 21.86 65.74 6.22 21.85 34 Pr Me H H H 66141˜142 C₁₅H₁₈N₄O i-Pr₂O 66.65 6.71 20.73 66.43 6.64 20.50 35 i-Pr H H HH 86 213.5˜215.5 C₁₄H₁₆N₄O EtOH 65.61 6.29 21.86 65.33 6.31 21.70 36i-Pr Me H H H 50 119˜122 C₁₅H₁₈N₄O i-Pr₂O 66.65 6.71 20.73 66.54 6.7320.67 37 i-Pr Et H H H 77 147 C₁₆H₂₀N₄O i-Pr₂O 67.58 7.09 19.70 67.477.05 19.62 38 i-Pr Ph H H H 55 192˜193 C₂₀H₂₀N₄O i-Pr₂O 71.49 6.12 16.6771.81 6.25 16.27 but 1/5H₂O adduct 39 i-Pr H Me H H 86 207˜208 C₁₅H₁₈N₄OEtOH 66.65 6.71 20.73 66.65 6.58 20.74 40 cyclo-Pr Me H H H 79 134C₁₅H₁₆N₄O i-Pr₂O 67.15 6.01 20.88 67.31 6.07 20.85

EXAMPLE 41 6-(2-Ethylpyrazolo[1,5-a]pyridine-3-yl)-5-methyl-3(2H)-pyridazinone

The compound (1.00 g) of Example 36 was dissolved into acetic acid (30ml), and, after adding bromine (0.22 ml) at 65° C. under stirring, themixture was stirred for 0.5 hours. The reaction liquor was poured intowater, which was extracted with methylene chloride. After the organiclayer was washed with water and with saturated aqueous solution ofsodium hydrogencarbonate and dried over anhydrous sodium sulfate,solvent was distilled off and the residue was purified by means ofsilica gel column chromatography (developing solvent, methylenechloride:ethanol=15:1) to obtain aimed product 0.69 g) as pale purplepowder. When recrystallizing from ethyl acetate, this gave pale purpleprismatic crystals.

Melting point: 216˜217° C.

Elemental analysis (%): As C₁₄H₁₄N₄O

C H N Calcd.: 66.13 5.55 22.03 Found: 65.96 5.49 21.90

EXAMPLES 42 AND 43

By conducting similarly to Example 41, following compounds were obtained(Table 5).

TABLE 5

Ex- Yield M.P. (° C.) Elemental analysis ample R¹ R² R⁴ (%) (Recryst.solvent) calcd./found 42 i-Pr H Me 71 216˜217 C₁₅H₁₆N₄O AcOEt 67.15 6.0120.88 66.95 5.97 20.82 43 i-Pr H H 73 225 C₁₄H₁₄N₄O AcOEt 65.66 5.5921.88 65.43 5.56 21.64 but 1/10H₂O adduct

EXAMPLE 44 (−)-6-(2-Isopropylpyrazolo[1,5-a]pyridine-3-yl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and(+)-6-(2-isopropylpyrazolo[1,5-a]pyridine-3-yl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone

The compound (1.31 g) of Example 36 was dissolved into 65 ml of mixedliquor of ethanol and hexane (1:4), and this solution was separatedautomatically by means of HPLC (optical resolution column: Chiralcell ODfrom Daicel Chemical Industries, Ltd., mobile layerhexane:isopropanol=9:1, injection 1 ml, flow rate 24 ml/min, detectingwavelength 293 nm). Compounds of each fraction obtained wererecrystallized from diisopropyl ether to obtain 530 mg of (−) form fromeluted fractions of front part and 560 mg of (+) form from elutedfractions of back part as colorless powder, respectively.

(−) Form Melting point 164˜165° C., Angle of rotation [α]_(D) ³⁴−179(C=0.24, CHCl₃)

Elemental analysis (%): As C₁₅H₁₈N₄O

C H N Calcd.: 66.66 6.71 20.73 Found: 66.50 6.64 20.67

(+) Form Melting point 164˜165° C., Angle of rotation [α]_(D) ³⁴+179(C=0.24, CHCl₃)

Elemental analysis (%): As C₁₅H₁₈N₄O

C H N Calcd.: 66.66 6.71 20.73 Found: 66.26 6.75 20.48

EXPERIMENTAL EXAMPLE

Measurement of phosphodiesterase-inhibiting activity

Phosphodiestorase-containing fractions were extracted from respiratorytract and heart of guinea pig according to the method of Nicholson et al(Br. J. Pharmacol., 97, 889-897 (1989)), and used as enzyme solutions.The measurement of phosphodiesterase-inhibiting activity was performedby quantitatively determining (Linden et al, J. Immunol. Methods., 151,209-216 (1992)) the cyclic AMP (cAMP) or cyclic GMP (cGMP) that remainsas a result of enzymic reaction (Thompson et al, Biochemistry, 10,311-316 (1971)) through enzyme immunoassay (EIA).

1) Enzymic reaction

This was performed according to the method of Thompson et al. The enzymesolution was placed in a test tube, and 1 μM of cAMP or cGMP was addedas a substrate. After reacting for 60 minutes at 30° C., the test tubewas dipped for 2 minutes into boiling bath to inactivatephosphodiesterase, thus stopping the reaction. The testing compound wasadded to the test tube simultaneously with substrate.

2) Quantitative determination through EIA

cAMP or cGMP that remained without undergoing decomposition by enzymesolution was quantitatively determined, using EIA kit (from Amasham Co.,England) for quantitative determination of CAMP or quantitativedetermination of cGMP to determine the amount of testing materialnecessary to inhibit the enzymic reaction by 50% as IC₅₀ the results ofwhich are shown in Table 6.

TABLE 6 IC₅₀ (μg/ml) Respiratory tract Heart II III IV V I II IIIExample 36 >30 4 5 0.1 >30 >30 5

Utilizability in the industry

The inventive compounds express selective inhibiting effect onphosphodiesterase originating from respiratory tract, in particular,phosphodiesterase V.

What is claimed is:
 1. A pyrazolopyridinepyridazinone derivativerepresented by the formula (1):

wherein R¹ is a cyclopropyl group, and R², R³, R⁴ and R⁵ are each,independently, a hydrogen atom, a lower alkyl group having 1 to 4 carbonatoms or a phenyl group, or R³ and R⁵ may combine to form a double bond,or a pharmacologically acceptable salt thereof.
 2. Thepyrazolopyridinepyridazinone derivative of claim 1, wherein R³ and R⁵combine to form a double bond.
 3. The pyrazolopyridinepyridazinonederivative of claim 1, wherein R², R³, R⁴ and R⁵ are each,independently, a hydrogen atom, a lower alkyl group having 1 to 4 carbonatoms or a phenyl group.
 4. A bronchodilator comprising at least onepyrazolopyridinepyridazinone derivative represented by the formula (1):

wherein R¹ is a cyclopropyl group, and R³, R³, R⁴ and R⁵ each,independently, represent a hydrogen atom, a lower alkyl group having of1 to 4 carbon atoms or a phenyl group, or R³ and R⁵ may combine to forma double bond, or a pharmacologically acceptable salt, as an effectiveingredient.
 5. The bronchodilator of claim 4, wherein R³ and R⁵ combineto form a double bond.
 6. The bronchodilator of claim 4, wherein R², R³,R⁴ and R⁵ are each, independently, a hydrogen atom, a lower alkyl grouphaving 1 to 4 carbon atoms or a phenyl group.
 7. A process for preparinga compound represented by the formula (1a):

wherein R¹ is a cyclopropyl group, and R⁴, R⁶ and R⁸ are each,independently, a hydrogen atom, a lower alkyl group having 1 to 4 carbonatoms or a phenyl group, comprising reacting a compounds represented bythe formula (6):

wherein R¹, R², R⁴, R⁶ and R⁸ are as described above, with hydrazine. 8.A method of inhibiting phosphodiesterase, comprising contacting aphosphodiesterase with the pyrazolopyridinepyridazinone derivative ofclaim 1.